The present invention is directed to biodegradable carriers for the delivery of therapeutic agents, methods of making the carriers and methods of using the carriers.
There is a clinical demand for carriers of therapeutic agents that are biodegradable, biocompatible and which allow for targeted delivery and controlled release of the therapeutic agent.
Polysaccharides, such as hyaluronic acid (HA) and dextran sulfate have been used in a wide variety of biomaterials. Hyaluronic acid (HA), a naturally occurring polysaccharide, has been used in matrix engineering in ophthalmic and orthopedic medicine. Clinical indications for HA alone are limited by its physical properties and the short residence time of the natural HA molecule. A formaldehyde cross-linked HA, Hylan, has been used in viscosupplementation of arthritic diseased joints (Takigami et al., 1993, Carbohydrate Polymers 22: 153-160). Dextran sulfate, a glycosaminoglycan-like polyionic derivative of dextran, has been shown to be useful as a biomaterial and drug for treatment of hyperlipidemia. It is produced by esterification of dextran, a hydrophilic polymer of glucose synthesized by certain strains of bacteria.
Berg et al., (U.S. Pat. No. 5,510,418, issued Apr. 4, 1996) disclose glycosaminoglycans, such as, HA, chondroitin sulfates, keratan sulfates, chitin and heparin, chemically conjugated to a synthetic hydrophilic polymer, such as polyethylene glycol (PEG) that are used as injectable formulations or solid implants. Koji Kimata et al., (U.S. Pat. No. 5,464,942 issued Nov. 7, 1995) disclose phospholipid linked glycosaminoglycans and their use as metastasis inhibitors. Sakurai, et al, U.S. Pat. No. 5,310,881 issued May 10, 1994, disclose glycosaminoglycan-modified proteins. Balazs et al., U.S. Pat. No. 5,128,326 issued Jul. 7, 1992, disclose hyaluronan cross-linked with divinyl sulfone.
The present invention provides biodegradable carriers for the delivery of therapeutic agents, methods of making the carriers and methods of using the carriers.
A biodegradable carrier of the present invention comprises a cross-linked first and second polysaccharide, wherein each of the first and the second polysaccharide is a derivative of a member selected from the group consisting of hyaluronic acid, dextran, dextran sulfate, chondroitin sulfate, dermatan sulfate, keratan sulfate, heparin, heparan sulfate and alginate. The first polysaccharide contains aldehyde groups derived from oxidized sugar rings. The second polysaccharide an amine derivative and the first and second polysaccharides are covalently cross-linked through these groups which forms imine linkages. In the present invention, the cross-linking reaction proceeds without utilizing extraneous cross-linking or ionic binding agents.
The method of making the biodegradable carriers comprises the steps of oxidizing a first polysaccharide to form a first polysaccharide derivative having aldehyde groups, and reacting the first polysaccharide derivative with a second polysaccharide amine derivative under conditions such that the aldehyde groups covalently react with the amine sites to form a cross linked carrier.
The present invention also provides methods of using the carrier to deliver therapeutic agents by administering the carrier at the sites of desired therapeutic intervention.
The ratios of the first and second polysaccharide can be varied to change both the physical and biological properties of the carrier. For example, a higher ratio of aldehyde bearing polysaccharide would be preferred for immobilizing a therapeutic agent to the carrier. The presence of unreacted but active aldehydes provides sites for covalent linkage to a therapeutic agent.
A carrier of the present invention can be produced in a variety of physical forms. For example, it can be made into a gel-like form for injection or a sponge-like form for implantation at a desired site of therapeutic intervention.
A carrier of the present invention provides the advantage of being biocompatible while maintaining a prolonged biodegradation rate due to the cross-linking; providing controlled release of the therapeutic agent and having the flexibility of formulation in gel-like or sponge-like form to accommodate desired therapeutic intervention.
As used herein therapeutic agent means any bioactive agent, such as a protein, polypeptide, or amino acid, including growth factors, growth factor receptors, cytokines, hormones, antibodies or chemical agents, such as, for example, non-peptide hormones chemical mimetics of growth factors and receptors that have been shown to have a biological effect.